SHARPIN

The Ubiquitin-like domain is required for the interaction with RNF31.

The RanBP2-type zinc fingers mediate the specific interaction with ubiquitin. Binds preferentially linear polyubiquitin chains and 'Lys-63'-linked polyubiquitin chains over 'Lys-48'-linked polyubiquitin chains. Also binds monoubiquitin.

Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation (PubMed:21455173, PubMed:21455180, PubMed:21455181). LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways (PubMed:21455173, PubMed:21455180, PubMed:21455181). Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation (PubMed:21455173, PubMed:21455180, PubMed:21455181). LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex (PubMed:21455173, PubMed:21455180, PubMed:21455181). The LUBAC complex is also involved in innate immunity by conjugating linear polyubiquitin chains at the surface of bacteria invading the cytosol to form the ubiquitin coat surrounding bacteria (PubMed:28481331). LUBAC is not able to initiate formation of the bacterial ubiquitin coat, and can only promote formation of linear polyubiquitins on pre-existing ubiquitin (PubMed:28481331). The bacterial ubiquitin coat acts as an 'eat-me' signal for xenophagy and promotes NF-kappa-B activation (PubMed:28481331). Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis (PubMed:23708998).

Autoinflammation with episodic fever and immune dysregulation

AIFID

An autosomal recessive disorder characterized by recurrent fever and autoinflammation with onset in infancy or early childhood. Variable clinical manifestations include lymphadenopathy, hepatosplenomegaly, gastrointestinal inflammation, polyarthritis and joint inflammation, parotitis, and immune dysregulation.

None

The disease is caused by variants affecting the gene represented in this entry.

Protein modification; protein ubiquitination.

Highly expressed in skeletal muscle and placenta and at lower levels in brain, heart, colon without mucosa, thymus, spleen, kidney, liver, small intestine, lung and peripheral blood leukocytes. Up-regulated in various tumor tissues such as kidney, liver, ovary and pancreas tumors.

• Cytoplasm
• Cytosol
• Synapse
• Enriched at synaptic sites in mature neurons where it colocalizes with SHANK1.

SIPL1, PSEC0216, SHARPIN, Sharpin, Shank-associated RH domain-interacting protein, Shank-interacting protein-like 1, hSIPL1

• entrezGene:81858
• omim:611885
• swissprot:Q9H0F6

Proteins

Neuroscience

39949Da